Pancreatic cancer is a serious health problem. In the United States alone, nearly 35,000 new cases are diagnosed annually and about same number of patients die of the disease. Difficulty in early diagnosis, rapid metastasis and intrinsic resistance to known chemical and radiation therapies represent major impediment in successful treatment of the disease. Elucidation of molecular pathways and tumor-encoded genes whose expression contribute to the intrinsic resistance and rapid metastasis of pancreatic cancer cells could yield immediate clinical benefits and reveal new therapeutic targets for effective control and treatment of pancreatic cancer. Observations: We recently found that: a) the majority of tumor samples from patients with pancreatic cancer and cancer cell lines express high basal levels of tissue transglutaminase (TG2). TG2 is a unique multifunctional protein implicated in cell adhesion, matrix-stabilization, wound healing, apoptosis and invasion;b) over expression of TG2 promotes constitutive activation of the focal adhesion kinase (FAK), Akt and NF-:B;c) inhibition of TG2 by small interfering RNA (siRNA) inhibited invasion and induced autophagic death in pancreatic cancer cells;conversely, d) ectopic expression of TG2 promoted cell survival and invasion;e) importantly, inhibition of TG2 by liposomal-siRNA significantly inhibited the growth and metastasis of orthotopically growing tumors in nude mice. Hypothesis: Based on these observations, we hypothesize that aberrant expression of TG2 contributes to the development of drug resistance and metastatic phenotype in pancreatic cancer cells. Specific aims: In Aim 1, we will determine the activity/function of TG2 that is necessary and/or sufficient for promoting drug resistance and invasion of pancreatic cancer cells whereas, studies proposed in Aim 2, will further substantiate our in vitro results and address the significance of elevated TG2 expression in promoting metastasis and chemoresistance of pancreatic tumor cells in vivo in a nude mouse model. The information obtained will substantiate the possibility of using TG2 as a therapeutic target for treatment of pancreatic cancer. PUBLIC HEALTH RELEVANCE: Studies proposed in this R21 application will help further substantiate our preliminary data on biological and therapeutic significance of increased tissue transglutaminase (TG2) expression in conferring chemoresistance and metastatic phenotypes on pancreatic cancer cells. Furthermore, the studies proposed will directly test the effect of TG2 on tumor growth, sensitivity to gemcitabine, and metastasis in orthotopically growing PDAC tumors in nude a nude mouse model.